Human parechovirus meningitis in children: state of the art

Human Parechovirus is a common cause of infection occurring especially during the first years of life. It may present with a broad spectrum of manifestations, ranging from a pauci-symptomatic infection to a sepsis-like or central nervous system disease. Aim of this study is to explore the knowledge on Parechovirus meningitis. According to the purpose of the study, a systematic review of the literature focusing on reports on central nervous system. Parechovirus infection of children was performed following PRISMA criteria. Out of the search, 304 papers were identified and 81 records were included in the revision dealing with epidemiology, clinical manifestations, laboratory findings, imaging, therapy and outcome. Parechovirus meningitis incidence may vary all over the world and outbreaks may occur. Fever is the most common symptom, followed by other non-specific signs and symptoms including irritability, poor feeding, skin rash or seizures. Although several reports describe favourable short-term neurodevelopmental outcomes at discharge after Parechovirus central nervous system infection, a specific follow up and the awareness on the risk of sequelae should be underlined in relation to the reported negative outcome. Evidence seems to suggest a correlation between magnetic imaging resonance alteration and a poor outcome.

of maternal protective antibodies and the immaturity of the immune system in toddlers may explain the potential danger related to HPeV infections in the youngest and the risk of sequelae [1].
Aim of the study is to review the current literature on HPeV meningitis in order to highlight the actual knowledge on epidemiology, clinical presentation, laboratory findings and imaging as well as therapeutic indication and need to follow up.

Introduction
Human Parechovirus (HPeV) is a common cause of infections occurring especially during the first years of life.It may present with a broad spectrum of manifestations, ranging from a pauci-symptomatic infection to a sepsis-like or central nervous system (CNS) disease, with possible neurological involvement, particularly among the youngest, that may even require intensive care unit assistance.The cytopathic effect, the rapid viral replication in neuronal cells, in combination with the likely lack used were "Parechovirus Meningitis", and filters were added to limit the research to a paediatric population (< 18 years old), to reports written in English, and to limit the time spam to the last 5 years (2018)(2019)(2020)(2021)(2022)(2023).Each research performed on each database was downloaded and then uploaded to the web tool "Rayyan web application" [3], a website used to analyse and appoint articles, specific for writing reviews.

Eligibility criteria
To be included in the review, reports should satisfy the following inclusion criteria: th February 2023.
The exclusion criteria are: − Issues not pertinent to the field of investigation; − Reports including adults, without age distinction; − Reports without data.

Selection process
The selection process was conducted following the PRISMA guidelines, and it was assisted using the web application "Rayyan" [3].First, the duplicates, produced by the research on four databases, were identified by the web application, Rayyan.Then, two authors checked the accuracy of the duplicates detected and excluded the unnecessary copies.
To limit errors and bias, two authors independently screened titles and abstracts produced by the research and defined those articles clearly irrelevant to the review.Afterward, full texts were retrieved and assessed for eligibility by the two screening authors.If full text articles couldn't be found, an attempt of contacting authors was performed, to obtain the full text.
Finally, following PRISMA guidelines, references not included in the original search but relevant to the review were examined.Disagreements regarding inclusion/ exclusion were settled through discussion between the researchers and a third author.

Data Collection process and data items
Relevant articles were selected on the web application Rayyan and grouped together based on the different issues they dealt with.
Afterwards, data was compiled in a Microsoft Excel spreadsheet to evaluate the main topics reported in the last years about HPeV meningitis.The information extracted from the full-text reports included epidemiological, clinical, laboratories, radiological, therapeutic data, and outcome results.

Data synthesis
Using the information gathered from the included studies, an updated review was achieved.The characteristics of the included studies were reported using descriptive statistics.No meta-analysis could be made with statistical work because of the variability of the studies.These results were then elaborated on in the discussion.

Results
The search of the selected electronic databases produced 304 studies.Diagram 1 presents the flow chart of the selection process, adapted from the PRISMA guidelines [4] (Fig. 1).
Out of them, 127 were the duplicates and 4 were not written in English.Then, according to PRISMA guidelines, all abstracts were analysed, and 63 records were discharged because they dealt with different topics, or with other types of HPeV infection, or with an adult population.Also, another duplicate article was found, not previously identified by the Rayyan web application.
Afterwards, 109 records were eligible to be analysed by reading their full-length text; however, 8 articles could not be retrieved.Therefore, 101 full-length reports were assessed for eligibility, and 21 were excluded because they did not display any data (n.15), or no age subgroups could be found in a study population including adults and children (n.5).In two cases the study reported had already been described in other articles.Finally, two relevant reports cited in other studies were added to this research.
In conclusion, 81 records were included in the revision.Table 1 below shows the main issues found in this scoping review.Epidemiology was discussed in 39 reports, clinical manifestations in 47 reports, laboratory findings in 36 reports, imaging in 23 reports, therapy in 11 reports and outcome in 24 reports.
Table 2 displays all the reports included and their major findings.

Epidemiology
Of 81 reports analysed, 39 dealt with the epidemiology of HPeV meningeal infection .
As well as for other Continents, in Oceania incidence was varying from 5,4% to 25,8%, depending on the case series and period time considered [38][39][40].Incidence of HPeV meningitis in the African continent seemed to be low.In Sudan, between December and August 2010 no patient was found positive for HPeV on CSF, out of 503 children aged 0 to 15 years presenting with fever, seizures, and a suspicion of neuroinfection [42].Nine years later in the Comoros archipelago, HPeV RT-PCR were performed on 122 CSFs, of which 77 were collected from children, and only a 30-days-aged infant presented with a CSF HPeV infection (0,8%) [43].The Countries involved in the studies are represented on the Map in Fig. 2.

Congenital HPeV Infection
Three cases of congenital/in utero transmission had been described in recent literature, leading to neonatal meningitis at birth, requiring intensive care unit support.The onset presentation symptoms were hypotonia, respiratory distress with desaturation, bradycardia, fever and abnormal movements [71][72][73].
General chemistry was unremarkable [41], although some authors described an increase of the transaminase, lactate dehydrogenase (LDH) values and hyponatremia [27,51,67,70].Retrospective study USA (America) In the period study, out of 251 patients, 0.4% of CSF was positive for HPeV Epidemiology Abedi GR, 2019 [6] Retrospective multicentre study USA (America) In the period study, 3.4% of children under the age of 1 year had CSF positive for HPeV Epidemiology Lee BR, 2020 [7] Retrospective cohort study USA (America) In the period study, out of 1926 specimens of CSF in children less than 6 months of age, 8.9% were positive for HPeV Epidemiology Clinical Presentation Laboratory Tomatis Souverbielle C, 2021 [8] Retrospective study USA (America) In the period study, out of 1475 infants younger than 60 days, 130 were HPeV positive.Infections mainly occurred in summer.Out of them, 96% had fever, 75% fussiness, and 29% a rash.In CSF, protein and glucose levels were within the normal ranges; 77% had no CSF pleocytosis.HPeV type 3 was the only one detected in CSF Epidemiology Clinical Presentation Sasidharan A, 2021 [9] Single-site study USA (America) In  [10] Retrospective study USA (America) In the period study, out of 14 patients with HPeV on CSF, 43% were infected in summer-fall and 57% in spring.Median age was 21 days, 57% were male.Symptoms were fever and fussiness (100%), poor oral intake (50%), seizures (7%).One out of 4 patients had abnormal MRI findings.Anti-epileptics medicines, corticosteroids and intravenous immunoglobulin were used in 2 patients with seizures.All the others received supportive care.

Ireland (Europe)
In the period study, there were 23 cases of CSF HPeV positive, all younger 2 months of age; 90% were serotype 3.No seasonality was found.Out of them, 90% was febrile, 40% irritable, 20% lethargic, 10% had seizures.None had CSF pleocytosis.Just 25% showed frontoparietal white matter changes at MRI.At 3 years follow up, 60% of patients had a normal development Epidemiology Clinical Presentation Laboratory Sano K, 2018 [27] Prospective study Japan (Asia) In the period study, over 56 febrile infants, 2 tested positive for HPeV on CSF.HPeV infections had a summer peak.Fever was the symptom of presentation.WBC count, platelets values and CSF pleocytosis rate was lower than in EV Epidemiology Clinical Presentation Imaging Outcome Abe Y, 2021 [28] Retrospective study Japan (Asia) In the period study, 34 out of 240 infants with HPeV infection had acute CNS involvement.87% were younger than 2 months of age, 87% presented with fever and 65.2% with seizures.57.1% presented with lesions on 15 months follow-up MRI.Half patients with abnormalities at MRI follow-up had neurological sequelae.Patients with normal MRI follow-up had no neurological sequelae Epidemiology Izumita R, 2019 [29] Prospective study Japan (Asia) In the period study, over 54 febrile neonates and young infants, HPeV was detected in serum and/or CSF of 14 patients Epidemiology Suziki Y, 2021 [30] Prospective study Japan (Asia) In the period study, 60/216 infants were found to have an HPeV infection on serum or CSF.HPeV type 3 was detected in 93% of cases, HPeV type 4 in 5% and 2% of untyped virus Epidemiology Laboratory Park SE, 2019 [31] Prospective cohort study Korea (Asia) In the period study, out of 90 children less than 1 year) of age with fever and sepsis-like signs, 10 had HPeV meningitis.In the CSF there was a significantly higher level of IL-2, IL-4, IL-7 and IL-13, than in controls Rhie S, 2020 [33] Retrospective study Korea (Asia) In the study period, 14 out of 161 CSF samples were HPeV-positive.All patients were younger than 3 months of age, 42.9% were male.All had fever.Compared to EV meningitis, patients had lower WCB count and lower rate of CSF pleocytosis Epidemiology Nam EJ, 2021 [34] Retrospective study Korea (Asia) In the study period, over 2230 CSF samples, 10 were positive for HPeV.They all aged less than 3 months.HPeV was found only in summer Epidemiology Chang JT, 2018 [35] Retrospective study Taiwan (Asia) In the study period, 1 out of 112 children aged less than 10 years and positive for HPeV was affected by HPeV meningitis Epidemiology Laboratory Nassrallah B, 2021 [36] Retrospective study Israel (Asia) In the study period, 5 out of 80 febrile infants aged less than 3 months had CSF positive for HPeV.Pleocytosis was absent in all Epidemiology Mathew S, 2021 [37] Retrospective study Qatar (Asia) In   Median age was 27 days, 62.5% were male, 7.8% had seizures, 32.5% abnormal findings on brain MRI (bilateral white matter signal changes and periventricular restricted diffusion patterns).In the second year of life, 63% (29/46) children showed developmental delay, which ameliorated by the third year of life (30%).Communication was the most common domain of concern Clinical Presentation Imaging Outcome Joseph L, 2019 [66] Retrospective study Australia (Oceania) Out of 77 patients, 87.5% were under 3 months, (37.2% neonates) and 56.4% male.9.7% of patients had seizures.15 out of 20 children had abnormal MRI findings (restricted diffusion in deep white matter); at follow-up 11 (14%) had neurodevelopmental delay Clinical Presentation Laboratory Imaging McKenna R, 2019 [67] Retrospective multicentre study Australia (Oceania) Patients admitted to ICU were all younger than 3 months, 93% had irritability, 57% apnoea, and 40% seizures.Lymphopenia was found in most of the cases.CRP values were low or mildly elevated.27% of patients had hyponatremia and 70% had increased transaminase values.Pleocytosis was absent, CSF protein level was normal and glucose values ranged from 2.3 to 6.7 mmol/L.78% of patients with white matter alterations on MRI developed severe diseases Clinical Presentation Imaging Therapy Midgley CM, 2018 [68] Retrospective study USA (America) 35 neonates presented with 91% fever, 2% hypothermia, 77% tachycardia, 77% poor feeding, 74% irritability, 26% rash, 20% seizures and 9% breathing difficulties.Brain MRI was performed in 3 infants who presented seizures, showing white matter abnormalities, EEG severe encephalopathy and multifocal epileptiform discharges in 2 cases.Acyclovir and anticonvulsant medication were administered in patients with seizures.Clinical Presentation Laboratory Therapy Kadambari S, 2019 [69] Prospective study UK (Europe) Out of 35 patients, 80% had fever, 66% poor feeding, 66% irritability, 51% lethargy, 29% rash.CSF WBC count was less than 20/mm 3 , serum CRP was low in 67% of cases.Empiric intravenous antibiotics were administered.46% of patients received acyclovir.One patient received intravenous immunoglobulin.Clinical Presentation Laboratory Outcome Roh DE, 2020 [70] Retrospective study Korea (Asia) 11 patients, median age of 41 days, presented with fever (100%), poor feeding (81.8%), irritability (63.6%), tachycardia (63.6%), tachypnoea (36.4%), apnoea (18.2%), seizures (9.1%).Blood tests showed a mean WBCc value of 5622/mmc.CRP e procalcitonin were low.Hyponatremia and mild transaminasemia were reported.Pleocytosis was absent.Protein and glucose values in CSF were normal.Hospitalisation was of 7.  Inflammation markers were generally in the range of normality or mildly elevated [1, 12, 18, 31, 41, 52, 53, 55-57, 63, 69, 70].Of note, compared with Enterovirus (EV) positive infants, infants with HPeV meningitis had lower values of blood white blood cells [27,33] and infection indices [17].

Cytokine Profile on serum and CSF
Measurement of cytokines levels revealed high levels of interleukins (IL): IL-6, IL-17 and TNF alpha on serum and of IL-2, IL-4, IL-7 and IL-13 in CSF [31,75].Compared to EV, a higher serum level of proinflammatory cytokine/chemokine was present in HPeV, likely related to the more severe clinical manifestations in the former [76].
Head ultrasound and cerebral magnetic resonance imaging (MRI) were the most used diagnostic exams; few cases reported head Computerised Tomography (CT) scan finding.

Magnetic resonance imaging
When performed in patients with HPeV neuro-infections, MRI resulted in white matter anomalies.Common findings included restricted diffusion in deep white matter and periventricular white matter involving mainly the frontal zones [48,50,65,6872].Involvement of parietal and temporal lobes, corpus callosum and thalamus have been described as well [58,71,73,77,78].Hyperintensity in the T2/FLAIR was also a possible presentation of HPeV neuro-infection [28].These findings were typically bilateral, either asymmetrical or symmetrical [50,58,65].Other findings, such as unilateral lesions, low signal intensity on T2 and hyperintensity on T1 or just a leptomeningeal enhancement were also described [28,50].Some authors reported that MRI abnormalities were usually detected in a minority of children with HPeV CSF infections [1,10,12,26,57,65].Conversely, other authors demonstrated that the majority of patients in the study populations had positive MRIs findings [28,66].
There's evidence that most of the patients with white matter alterations on MRI developed more severe diseases, with seizures or necessity of ventilations and vasoactive infusion [67].
When performed weeks or months after the acute infection, MRI scan might be normal, with no evidence of white matter lesions [49,58].Persistence of the lesions had been proved in a minority of patients [28,65].
White matter MRI anomaly had been also used as a prognostic sign of neurodevelopmental concerns.By the way, some authors found neurodevelopmental impairment at clinical follow-up in children with initial MRI alterations [28,65,66].
Bucci S. et al. showed that children with MRI abnormalities in the HPeV acute infection scored lower, but still in the range of normality, on cognitive Bayley III (Bayley Scales of Infant and Toddler Development, Third Edition) subscale at Neurodevelopmental assessment at 1 year of age compared with children with normal MRI [25].Whereas Abe Y. et al. reported that the totality of the patients (6/6) with MRI negative findings had a neurological good prognosis [28].
In case of critical conditions or unresponsiveness to therapy, intravenous immunoglobulin and/or methylprednisolone have been prescribed [10,21,50,69].Finally, posaconazole was used against HPeV type 3, acting as an early-stage inhibitor of viral replication: it binds the capsid interfering with virus-cell attachment and entry [79].
Hospitalisation ranged from 2 days to 5 weeks.The high variability was depending on various factors, including the clinical course and the need of intensive care in case of respiratory distress, apnoea, seizures, and hemodynamic instability [1,12,21,48,49,56,57,62,70].
All but one otherwise healthy 11-days old neonate affected by HPeV type 3 meningoencephalitis survived.The neonate's autopsy showed bilateral multicystic cavitation of the fronto-parietal white matter as well of temporal and occipital asymmetric cavitation [78].

Long-term outcome
The long-term outcome was analysed in 21 reports.
Even if HPeV is one of the main identified etiological agents of viral meningitis in infants, poor attention has been reserved to it from the Scientific Community in the past, mainly due to the high survival range.Examining scientific reports from all over the world are increasing awareness of the risk connected to a severe parechovirus infection.In fact, out of the revised literature, cerebral palsy, vision and neuropsychomotor development impairment were reported in a high percentage of case series [65,80,83].The appropriate duration of post hospitalisation follow-up is still being debated.Evidence supported clinical follow-up until at least the second year of life, with a recommended longer-term follow-up in case of further potential risk factors, such as prematurity, early onset of infection (neonatal period), MRI abnormalities, severe clinical course (seizures, apnoea) with necessity of paediatric Intensive Care Unit [1,25,28,48,6566].Evidence suggested an ameliorating of clinical sequelae with a normal development in most cases by the age of three [65].Anyway, as neurodevelopmental impairment is often difficult to detach at an early stage, prior to schoolage, families should be aware of potential neurological, behavioural, and learning impairments in childhood in order to eventually seek assessment.

Conclusion
HPeV infection is very common in paediatric age and may have a severe course mainly among neonates and toddlers less than 3 months of age when it manifests as meningitis.Symptoms may be non-specific, including fever, irritability, poor feeding, skin rash, or seizures.Although several authors described favourable outcome with high probability of survival, reported neurodevelopmental outcomes at discharge suggest a specific follow up and the family awareness on the risk of sequelae.
Evidence supported clinical follow-up until at least the second year of life, with a recommended longerterm follow-up in case of further potential risk factors, such as prematurity, early onset of infection (neonatal period), MRI abnormalities, severe clinical course (seizures, apnoea) with necessity of paediatric Intensive Care Unit.Of note, we emphasise the need for surveillance to define the disease burden, evaluate strategies and interventions to prevent and manage cases, and to respond to the potential first early signals of sequelae developing.Finally, defying and following the global epidemiology of HPeV infection may be useful for considering the opportunity of vaccine development mainly for those with risk factors for a severe course.

Fig. 1
Fig. 1 Flow chart of the selection process

Fig. 2
Fig. 2 Countries involved in the studies are shown in blue on the World map.They were Argentina, Australia, Canada, Comoros, France, Germany, Greece, Ireland, Israel, Italy, Japan, Netherlands, New Zealand, Poland, Portugal, Qatar, Singapore, South Korea, Spain, Sudan, Taiwan, Turkey, United Kingdom., USA.

Table 1
Main issues found in this scoping review the period study, out of 5255 CSF samples, two were HPeV positive

Table 2
Reports included and the major finding In the period study, out of 1373 CSF specimens, 34 tested positive for HPeV.No seasonality was observed.97% were under 3 months of age, 100% presented with fever, 13% had an erythematous and maculopapular rash, 23% had diarrhoea.Pleocytosis was observed in 11% of cases, lower than in case of

Table 2
(continued) the study period, HPeV was isolated in 26 out 30 children aged less than 9 presented with sepsis-like symptoms, elevated serum CRP, mild pleocytosis, low level of proteins and normal values of glucose in CSF.Head ultrasounds was normal, MRI showed bifrontal periventricular abnormalities of the white matter.He was discharged at 37 weeks and 6 days of life.At 5 years follow up the patient presented with cerebral palsy, vision, and psychomotor development impairment

Table 2
(continued) A 38-day-old infant with sepsis-like condition, fever and rash had normal WBC count on CSF and blood, low haemoglobin value, normal biochemical parameters, and CRP mildly elevated.Head ultrasound was normal.He received intravenous antibiotics and acyclovir.hospitalisation was 6 days long